bms-790052 and Cryoglobulinemia

Direct-acting antivirals (DAAs) dramatically improve the treatment of hepatitis C virus (HCV) infections. However, the effects of DAAs on extra-hepatic manifestations such as HCV-associated glomerulonephritis, especially in cases with renal dysfunction, are not well elucidated.. A 69-year-old Japanese woman was diagnosed as having chronic hepatitis C, genotype 1b at the age of 55. She presented with hypertension, microscopic hematuria, proteinuria, renal dysfunction, purpura, and arthralgia at the age of 61. She also had hypocomplementemia and cryoglobulinemia. Renal biopsy revealed membranoproliferative glomerulonephritis (MPGN), and she was diagnosed as having HCV-associated cryoglobulinemic MPGN. She declined interferon therapy at the time and was treated with antihypertensive medications as well as oral corticosteroid that were effective in reducing proteinuria. However, when the corticosteroid dose was reduced, proteinuria worsened. She began antiviral treatment with daclatasvir/asunaprevir (DCV/ASV). Clearance of HCV-RNA was obtained by 2 weeks and sustained, and liver function was normalized. In addition, microhematuria turned negative, proteinuria decreased, hypocomplementemia and estimated glomerular filtration rate were improved, whereas cryoglobulinemia persisted. She completed 24 weeks of therapy without significant adverse effects.. In a case of HCV-associated cryoglobulinemic MPGN with renal dysfunction, DCV/ASV -based DAAs ameliorated microhematuria, proteinuria and renal function without significant side effects.

Topics: Aged; Antiviral Agents; Carbamates; Cryoglobulinemia; Female; Glomerulonephritis, Membranoproliferative; Hepatitis C; Humans; Imidazoles; Isoquinolines; Pyrrolidines; Sulfonamides; Treatment Outcome; Valine

Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C (CHC), with the presence of symptoms in 10-15% of cases. There have been encouraging data regarding immunological and clinical responses in patients treated with the novel combinations of direct-acting antivirals (DAAs), but the role of ribavirin (RBV) in the treatment of MC has not yet been demonstrated. We prospectively enrolled 132 patients affected by MC and CHC, and virological, immunological and clinical responses were evaluated at 12 weeks after completion of treatment. All subjects were treated with interferon (IFN)-free regimens according to clinical guidelines, with or without RBV. All patients achieved a virological response. A complete immunological response (CR) was observed in 71 subjects (53.8%), a partial response in 44 (33.3%), and no response in 17 (12.8%). Ten patients showed a complete resolution of symptoms (7.6%), and 31 showed a significant improvement (23.5%). CR was significantly higher in patients taking RBV (71.1 vs. 44.8%, p < 0.001) and in treatment-naïve patients (62.5 vs. 43.3%, p < 0.001). In logistic regression analysis, duration of HCV infection of less than 20 years (OR 2.448; 95% IC 1.335-6.202; p = 0.019), treatment-naïve status (OR 2.885; 95% IC 1.404-9.660; p = 0.025) and the use of RBV (OR 6.961; 95% IC 3.912-26.885; p < 0.001) were predictors of CR. In MC patients, IFN-free regimens are effective and well tolerated, and RBV seems to significantly increase the immunological response and promote a decline in cryocrit.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cryoglobulinemia; Cyclopropanes; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Prospective Studies; Pyrrolidines; Ribavirin; Ritonavir; Sofosbuvir; Sulfonamides; Treatment Outcome; Uracil; Valine

Direct antivirals showed dramatic response in hepatitis C virus (HCV) eradication, but their effect on extrahepatic manifestations is still unclear. A 49-year-old woman was referred to us suffering from lower limb edema and frothy urine. Renal biopsy was done and she was diagnosed with HCV-related membranoproliferative glomerulonephritis with cryoglobulinemia. Treatment with interferon plus ribavirin, steroid, and cyclophosphamide was tried but failed. After introduction of a sofosbuvir-based regimen to the treatment, sustained virologic response was achieved and nephrotic syndrome remission was induced successfully. We could conclude that HCV-related membranoproliferative glomerulonephritis with cryoglobulinemia could be treated successfully with immunosuppressive drugs plus sofosbuvir and dacalatasvir.

Topics: Antiviral Agents; Carbamates; Cryoglobulinemia; Drug Therapy, Combination; Female; Glomerulonephritis, Membranoproliferative; Hepacivirus; Hepatitis C; Humans; Imidazoles; Middle Aged; Pyrrolidines; Sofosbuvir; Treatment Outcome; Valine

Interferon-free direct-acting antiviral (DAA) therapies are effective in patients with hepatitis C virus-induced cryoglobulinemia vasculitis (HCV-CV). We analyzed blood samples from patients with HCV-CV before and after DAA therapy to determine mechanisms of these drugs and their effects on cellular immunity.. We performed a prospective study of 27 consecutive patients with HCV-CV (median age, 59 y) treated with DAA therapy (21 patients received sofosbuvir plus ribavirin for 24 weeks, 4 patients received sofosbuvir plus daclatasvir for 12 weeks, and 2 patients received sofosbuvir plus simeprevir for 12 weeks) in Paris, France. Blood samples were collected from these patients before and after DAA therapy, and also from 12 healthy donors and 12 individuals with HCV infection without CV. HCV load, cryoglobulins, and cytokines were quantified by flow cytometry, cytokine multiplex assays, and enzyme-linked immunosorbent assay.. Twenty-four patients (88.9%) had a complete clinical response of CV to DAA therapy at week 24, defined by improvement of all the affected organs and the absence of relapse. Compared with healthy donors and patients with HCV infection without CV, patients with HCV-CV, before DAA therapy, had a lower percentage of CD4+CD25hiFoxP3+ regulatory T cells (P < .01), but higher proportions of IgM+CD21-/low memory B cells (P < .05), CD4+IFNγ+ cells (P < .01), CD4+IL17A+ cells (P < .01), and CD4+CXCR5+interleukin 21+ follicular T-helper (Tfh) cells (P < .01). In patients with HCV-CV, there was a negative correlation between numbers of IgM+CD21-/low memory B cells and T-regulatory cells (P = .03), and positive correlations with numbers of Tfh cells (P = .03) and serum levels of cryoglobulin (P = .01). DAA therapy increased patients' numbers of T-regulatory cells (1.5% ± 0.18% before therapy vs 2.1% ± 0.18% after therapy), decreased percentages of IgM+CD21-/low memory B cells (35.7% ± 6.1% before therapy vs 14.9% ± 3.8% after therapy), and decreased numbers of Tfh cells (12% ± 1.3% before therapy vs 8% ± 0.9% after therapy). Expression levels of B lymphocyte stimulator receptor 3 and programmed cell death 1 on B cells increased in patients with HCV-CV after DAA-based therapy (mean fluorescence units, 37 ± 2.4 before therapy vs 47 ± 2.6 after therapy, P < .01; and 29 ± 7.3 before therapy vs 48 ± 9.3 after therapy, P < .05, respectively).. In a prospective clinical trial of patients with HCV-CV, DAA-based therapy restored disturbances in peripheral B- and T-cell homeostasis.

Topics: Aged; Antiviral Agents; B-Lymphocyte Subsets; Biomarkers; Carbamates; Case-Control Studies; Cryoglobulinemia; Cytokines; Drug Therapy, Combination; Female; Hepatitis C; Hepatitis Viruses; Humans; Imidazoles; Immune Tolerance; Immunity, Cellular; Male; Middle Aged; Phenotype; Prospective Studies; Pyrrolidines; Ribavirin; Simeprevir; Sofosbuvir; T-Lymphocyte Subsets; Time Factors; Treatment Outcome; Valine; Vasculitis; Viral Load

Circulating mixed cryoglobulins are detected in 40%-60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in approximately 15% of patients. Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct-acting antiviral drugs in these patients. We performed an open-label, prospective, multicenter study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 y; 53.6% women) were recruited from hospitals in Paris, France, from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n = 32) or 24 weeks (n = 9), and were evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks of therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients' mean cryoglobulin level decreased from 0.56 ± 0.18 at baseline to 0.21 ± 0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21-/low-memory B cells, CD4+CXCR5+ interleukin 21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20-30 mo), no patients had a serious adverse event or relapse of vasculitis.

Topics: Antiviral Agents; B-Lymphocytes; Carbamates; CD4-Positive T-Lymphocytes; Cryoglobulinemia; Cryoglobulins; Drug Therapy, Combination; Female; Hepatitis C; Humans; Imidazoles; Immunoglobulin M; Interleukins; Lymphocyte Count; Male; Middle Aged; Prospective Studies; Pyrrolidines; Receptors, Complement 3d; Receptors, CXCR5; Sofosbuvir; Sustained Virologic Response; T-Lymphocytes, Regulatory; Th17 Cells; Valine; Vasculitis